Reviewed: Terburg D, Syal S, Rosenberger LA, et al. Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus. Neuropsychopharmacology. August 2013; [epub ahead of print]. doi: 10.1038/npp.2013.183.
Sceletium (Sceletium tortuosum, Aizoaceae) is a plant indigenous to South Africa with psychotropic (mood-altering) properties. Preliminary studies suggest that it may help allieviate anxiety and depression. Sceletium has been reported to work by inhibiting serotonin (5-hydroxytryptamine; 5-HT) reuptake transporters and selectively inhibiting phosphodiesterase-4 (PDE4) enzyme subtypes in the central nervous system (CNS). These actions may be synergistic. Many conventional pharmaceuticals that treat anxiety and/or depression work on the 5-HT transporter; however, inhibition of PDE4 enzymes would be a new mechanism for psychotherapeutic drugs, and preliminary animal data look promising.
The amygdala is an area of the brain associated with threat detection and regulation of fear and anxiety. Researchers can assess acute anxiety by conducting functional magnetic resonance imaging (fMRI) of the brain to measure anxiety-related amygdala activation, and the subsequent connectivity of the amygdala with the cortical and/or subcortical threat circuit. Hence, the purpose of this small, double-blind, placebo-controlled, crossover study was to evaluate the acute anxiolytic effects of a single dose of sceletium extract during amygdala neurocircuitry stimulation.
The study included healthy undergraduate students (n=16, aged 18 to 21 years, with equal participants of both sexes) from the University of Cape Town in South Africa who were right-handed, non-medicated, had no history of neurological disease or psychopathology, and had normal or corrected-to-normal vision. Subjects received either sceletium (25 mg Zembrin®; HG&H Pharmaceuticals; Bryanston, South Africa) or placebo two hours prior to undergoing the fMRI scan.
Zembrin is a standardized extract of the aerial plant parts of sceletium extracted with 70% ethanol, which is spray-dried onto maltodextrin. It contains four active alkaloids, including: mesembrenone, mesembrenol, mesembranol, and mesembrine. Each tablet contains the equivalent of material derived from 50 mg of the dried aboveground plant. There was a five-to-nine day washout period between treatments for each subject. During the scan, subjects performed the two following tasks: the perceptual-load task (PLT) and the emotion-matching task (EMT). The PLT assesses anxiety-related amygdala activity (subjects identify letters on faces that are either neutral or with a fearful expression to induce anxiety). The EMT is a reliable amygdala activator (subjects match either ovals or faces expressing anger or fear) and is used to assess amygdala-hypothalamus coupling.
During the PLT test, amygdala reactivity to facial fear under low-load conditions was significantly reduced after sceletium administration compared with placebo (P=0.020). As expected, the EMT test showed activation of the midbrain, hypothalamus, amygdala, and ventro-medial prefrontal cortex/orbitofrontal cortex (vmPFC/OFC). During the EMT test, there was a significant decrease in functional connectivity between the amygdala and the hypothalamus after sceletium administration compared with placebo (P=0.034). Sceletium treatment did not affect the connectivity between the amygdala and the midbrain or vmPFC/OFC. No general subjective mood effects were observed.
The authors conclude that Zembrin, compared to placebo administration, reduces anxiety-related amygdala reactivity and decreases amygdala-hypothalamus coupling in the subcortical threat circuit. Although there were no general subjective mood effects, the authors state that the effects reflect a reduction of responsiveness of the threat system related to the anxiolytic properties of sceletium. These results help support sceletium’s proposed neurological mechanism of action and provide further rationale for exploring potential therapeutic efficacy in future clinical trials.